Sickle cell disease (SCD) is the most common hemoglobin mutation in the US, affecting 60,000 people. SCD is often associated with focal brain abnormalities that worsen as the disease progresses, and conventional MRI (cMRI) can demonstrate focal damage even in infants. At least 1 in 4 SCD patients show cMRI evidence of focal abnormality by age 20. However, we hypothesize that diffuse brain abnormality is actually more common than focal damage, and that it usually precedes focal damage. Because diffuse abnormality cannot be well-visualized by cMRI methods, the prevalence of diffuse abnormality is not known. Our goal is to determine whether new quantitative MRI (qMRI) methods are more sensitive than cMRI methods to diffuse brain damage in SCD patients, and to ascertain whether diffuse brain abnormality correlates with the clinical course of disease. We will use qMRI methods developed in our lab, in a prospective, longitudinal, clinical study of young SCD patients. We will enroll 50 patients and 50 sibling controls, and follow all enrolled subjects prospectively for 5 years. We will use T1 mapping and quantitative MR angiography (qMRA), to characterize the prevalence and to evaluate the significance of diffuse brain abnormality in pediatric SCD patients. Data from cMRI, qMRI and qMRA will be correlated with clinical and psychometric data, to determine which MR imaging data are predictive of clinical severity or development of cognitive deficits. To be specific, we will: characterize the relationship between diffuse T1 reduction and focal brain abnormality detected by cMRI; determine if diffuse T1 reduction is associated with subtle loss of gray or white matter volume measured by cMRI image segmentation; ascertain if diffuse T1 reduction is correlated with psychometric deficit; and establish whether diffuse T1 reduction is associated with vasculopathy, including ectasia or stenosis of the cranial arteries. Because infarctive stroke risk in young SCD patients is 6-fold higher than in healthy adults, SCD patients may provide a clinical model for the most common type of stroke in elderly adults. We will establish whether these novel qMRI methods provide a sensitive and clinically-relevant indicator of diffuse brain injury. Our long- range goal is to determine the mechanisms causing cognitive loss in SCD patients, in an effort to determine a therapeutic strategy to minimize such damage in these patients.